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The activation of the protein kinase C (PKC) family of serine/threonine kinases contributes to the modulation of insulin signaling, and the PKC-dependent phosphorylation of insulin receptor substrate (IRS)-1 has been implicated in the development of insulin resistance. Here we demonstrate Ser357 of rat IRS-1 as a novel PKC-δ-dependent phosphorylation site in skeletal muscle cells upon stimulation with insulin and phorbol ester using Ser(P)357 antibodies and active and kinase dead mutants of PKC-δ. Phosphorylation of this site was simulated using IRS-1 Glu357 and shown to reduce insulin-induced tyrosine phosphorylation of IRS-1, to decrease activation of Akt, and to subsequently diminish phosphorylation of glycogen synthase kinase-3. When the phosphorylation was prevented by mutation of Ser357 to alanine, these effects of insulin were enhanced. When the adjacent Ser358, present in mouse and rat IRS-1, was mutated to alanine, which is homologous to the human sequence, the insulin-induced phosphorylation of glycogen synthase kinase-3 or tyrosine phosphorylation of IRS-1 was not increased. Moreover, both active PKC-δ and phosphorylation of Ser357 were shown to be necessary for the attenuation of insulin-stimulated Akt phosphorylation. The phosphorylation of Ser357 could lead to increased association of PKC-δ to IRS-1 upon insulin stimulation, which was demonstrated with IRS-1 Glu357. Together, these data suggest that phosphorylation of Ser357 mediates at least in part the adverse effects of PKC-δ activation on insulin action.